rs3746190

Positions:

• chr19-18059574-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005535.3(IL12RB1):​c.*34C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 778,530 control chromosomes in the GnomAD database, including 45,881 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (7318 hom., cov: 32)
  • Exomes 𝑓: 0.34 (38563 hom.)
• Consequence: IL12RB1 NM_005535.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.00200

Genes affected

IL12RB1 (HGNC:5971): (interleukin 12 receptor subunit beta 1) The protein encoded by this gene is a type I transmembrane protein that belongs to the hemopoietin receptor superfamily. This protein binds to interleukine 12 (IL12) with a low affinity, and is thought to be a part of IL12 receptor complex. This protein forms a disulfide-linked oligomer, which is required for its IL12 binding activity. The coexpression of this and IL12RB2 proteins was shown to lead to the formation of high-affinity IL12 binding sites and reconstitution of IL12 dependent signaling. Mutations in this gene impair the development of interleukin-17-producing T lymphocytes and result in increased susceptibility to mycobacterial and Salmonella infections. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-18059574-G-A is Benign according to our data. Variant chr19-18059574-G-A is described in ClinVar as [Benign]. Clinvar id is 328572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL12RB1	NM_005535.3	c.*34C>T		3_prime_UTR_variant	17/17	ENST00000593993.7	NP_005526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL12RB1	ENST00000593993.7	c.*34C>T		3_prime_UTR_variant	17/17	1	NM_005535.3	ENSP00000472165	P1
IL12RB1	ENST00000600835.6	c.*34C>T		3_prime_UTR_variant	18/18	1		ENSP00000470788	P1

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42868 AN: 151944 Hom.: 7318 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.344

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.470

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.387

Gnomad OTH AF: 0.283

GnomAD3 exomes AF: 0.302 AC: 73419 AN: 243418 Hom.: 12488 AF XY: 0.308 AC XY: 40706 AN XY: 132174

Gnomad AFR exome AF: 0.0983

Gnomad AMR exome AF: 0.189

Gnomad ASJ exome AF: 0.337

Gnomad EAS exome AF: 0.115

Gnomad SAS exome AF: 0.222

Gnomad FIN exome AF: 0.455

Gnomad NFE exome AF: 0.384

Gnomad OTH exome AF: 0.329

GnomAD4 exome AF: 0.338 AC: 211489 AN: 626468 Hom.: 38563 Cov.: 0 AF XY: 0.336 AC XY: 114603 AN XY: 341138

Gnomad4 AFR exome AF: 0.103

Gnomad4 AMR exome AF: 0.193

Gnomad4 ASJ exome AF: 0.340

Gnomad4 EAS exome AF: 0.190

Gnomad4 SAS exome AF: 0.231

Gnomad4 FIN exome AF: 0.451

Gnomad4 NFE exome AF: 0.387

Gnomad4 OTH exome AF: 0.334

GnomAD4 genome AF: 0.282 AC: 42867 AN: 152062 Hom.: 7318 Cov.: 32 AF XY: 0.284 AC XY: 21085 AN XY: 74308

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.221

Gnomad4 ASJ AF: 0.344

Gnomad4 EAS AF: 0.135

Gnomad4 SAS AF: 0.230

Gnomad4 FIN AF: 0.470

Gnomad4 NFE AF: 0.387

Gnomad4 OTH AF: 0.279

Alfa AF: 0.319 Hom.: 1912

Bravo AF: 0.255

Asia WGS AF: 0.169 AC: 593 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 50% of patients studied by a panel of primary immunodeficiencies. Number of patients: 44. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.3
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3746190; hg19: chr19-18170384; COSMIC: COSV74045533;